A Critical Analysis of the Clinical Use of Incretin-Based Therapies: Efficacy and Adverse Events

TL;DR

Incretin-based therapies like GLP-1 and GIP agonists show promise for treating obesity and diabetes but come with side effects and limited long-term safety data.

Contribution

This paper critically analyzes the clinical efficacy and safety profile of incretin-based therapies, highlighting their expanding roles and limitations.

Findings

GLP-1 and GIP agonists like semaglutide and tirzepatide significantly reduce weight and improve glycemic control.

Tirzepatide outperforms semaglutide in weight loss due to dual-receptor activation.

Adverse effects include gastrointestinal issues and potential risks for gallbladder disease or pancreatitis.

Abstract

Obesity is a major public health challenge in the United States, despite widespread implementation of regulated diet plans, exercise programs, behavioral interventions, and surgical procedures. The emergence of incretin-based therapies, particularly GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) receptor agonists, has transformed the therapeutic landscape for initially type 2 diabetes and now obesity. Beyond their metabolic effects, incretin therapies exert meaningful cardiovascular, gastrointestinal, and neuroprotective actions. Semaglutide, a GLP-1 receptor agonist, and tripeptide, a dual GLP-1/GIP agonist, demonstrate substantial weight reduction, improved glycemic control, and reductions in cardiometabolic risk factors. Tirzepatide consistently produces greater weight loss effects than semaglutide, likely due to synergistic dual-receptor effects. However, these therapies are accompanied by adverse effects, most commonly gastrointestinal disturbances, and, less frequently, gallbladder disease, pancreatitis, or rare ophthalmologic concerns. Long-term safety data remain limited, particularly in older adults, pediatric patients, pregnant women, and individuals with comorbid disease. Emerging evidence also suggests potential roles in cancer prevention, hypertension, and neurodegenerative disease. As the indications for incretin-based therapies continue to expand, longer-duration trials and more diverse study populations will be essential to fully examine their long-term clinical effects. Though these agents hold considerable promise, careful and informed use remain vital.

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